Previously, we cloned and characterized two pharmacologically distinct bombesin receptors (GRP-R and NMB-R) with high affinity for gastrin- releasing peptide (GRP) or neuromedin B (NMB), respectively. Recently, we isolated and characterized a third distinct mammalian receptor for bombesin peptides (BRS-3) from cultured human lung cancer cells, This receptor is specifically activated by bombesin peptides after expression in Xenopus oocytes. However, higher concentrations of peptide (greater than 1 micromole) are needed to reproducibly elicit the response, indicating that a high-affinity bombesin ligand has not as yet been determined for BRS-3. Receptor activation results in elevation of intracellular calcium, presumably coupling through a G-g-like hetertrimeric G-protein which activates phospholipase C-beta 1. BRS-3 is selectively expressed in human lung cancer cells and secondary spermatocytes, but neither in the GI tract nor CNS, and maps to human chromosome X. Receptor chimeras constructed between the GRP-R and NMB-R map the domain responsible for high-affinity NMB-binding and effector signalling to transmembrane segment 5.